Review
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 28, 2017; 23(12): 2106-2123
Published online Mar 28, 2017. doi: 10.3748/wjg.v23.i12.2106
Regulation of intestinal permeability: The role of proteases
Hanne Van Spaendonk, Hannah Ceuleers, Leonie Witters, Eveline Patteet, Jurgen Joossens, Koen Augustyns, Anne-Marie Lambeir, Ingrid De Meester, Joris G De Man, Benedicte Y De Winter
Hanne Van Spaendonk, Hannah Ceuleers, Leonie Witters, Eveline Patteet, Joris G De Man, Benedicte Y De Winter, Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, 2610 Antwerp, Belgium
Jurgen Joossens, Koen Augustyns, Laboratory of Medicinal Chemistry and Antwerp Drug Discovery Network, University of Antwerp, 2610 Antwerp, Belgium
Anne-Marie Lambeir, Ingrid De Meester, Laboratory of Medical Biochemistry, University of Antwerp, 2610 Antwerp, Belgium
Author contributions: All authors contributed equally to this paper with conception and design of the study, literature review and analysis, drafting and critical review and editing and approval of the final version.
Supported by University of Antwerp, No. GOA 2013.
Conflict-of-interest statement: No potential conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Benedicte Y De Winter, Professor, MD, PhD, Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. benedicte.dewinter@uantwerpen.be
Telephone: + 32-3-2652710 Fax: + 32-3-2652567
Received: September 26, 2016
Peer-review started: September 27, 2016
First decision: December 19, 2016
Revised: January 20, 2017
Accepted: March 2, 2017
Article in press: March 2, 2017
Published online: March 28, 2017
Processing time: 182 Days and 11.3 Hours
Abstract

The gastrointestinal barrier is - with approximately 400 m2 - the human body’s largest surface separating the external environment from the internal milieu. This barrier serves a dual function: permitting the absorption of nutrients, water and electrolytes on the one hand, while limiting host contact with noxious luminal antigens on the other hand. To maintain this selective barrier, junction protein complexes seal the intercellular space between adjacent epithelial cells and regulate the paracellular transport. Increased intestinal permeability is associated with and suggested as a player in the pathophysiology of various gastrointestinal and extra-intestinal diseases such as inflammatory bowel disease, celiac disease and type 1 diabetes. The gastrointestinal tract is exposed to high levels of endogenous and exogenous proteases, both in the lumen and in the mucosa. There is increasing evidence to suggest that a dysregulation of the protease/antiprotease balance in the gut contributes to epithelial damage and increased permeability. Excessive proteolysis leads to direct cleavage of intercellular junction proteins, or to opening of the junction proteins via activation of protease activated receptors. In addition, proteases regulate the activity and availability of cytokines and growth factors, which are also known modulators of intestinal permeability. This review aims at outlining the mechanisms by which proteases alter the intestinal permeability. More knowledge on the role of proteases in mucosal homeostasis and gastrointestinal barrier function will definitely contribute to the identification of new therapeutic targets for permeability-related diseases.

Keywords: Intestinal permeability; Intestinal barrier; Tight junction; Paracellular permeability; Proteases; Proteinase-activated receptor; Protease inhibitor; Antiproteases

Core tip: Increased intestinal permeability is a novel player in the pathophysiology of various intestinal and extra-intestinal diseases such as inflammatory bowel disease, celiac disease and type 1 diabetes. A dysregulated protease/antiproteases balance is suggested as a cause of intestinal barrier dysfunction, with a subsequent increase in permeability. Immune cells infiltrating in the lamina propria during inflammatory conditions provide a pro-inflammatory environment by the production of cytokines and proteases. Protease inhibition has therapeutic potential but more research is needed to elucidate the exact involvement of specific proteases in gut physiology and intestinal barrier function.